In the medical industry, there is often a need for a laboratory technician, e.g., a cytotechnologist, to review a cytological specimen for the presence of specified cell types. For example, there is presently a need to review a cervico-vaginal Papanicolaou (Pap) smear slides for the presence of malignant or pre-malignant cells. Since its introduction over fifty years ago, Pap smears have been a powerful tool for detecting cancerous and precancerous cervical lesions. During that time, the Pap smear has been credited with reducing mortality from cervical cancer by as much as 70%. This once precipitous drop in the death rate has slowed however, and the mortality rate in the United States for this preventable disease has remained virtually constant, at about 5,000 per year since the mid-eighties. Therefore, about one-third of the 15,000 women diagnosed with cervical cancer annually still die, because the cancer was detected too late. A further cause for concern is National Cancer Institute data that shows an annual 3% increase in the incidence of invasive cervical cancer in white women under 50 years of age since 1986.
A number of factors may be contributing to this current threshold, not the least of which is the fact that many women, particularly in high risk populations, are still not participating in routine cervical cancer screening. Another contributing factor that has received much attention is the limitation of the traditional Pap smear method itself.
The reliability and efficacy of a cervical screening method is measured by its ability to diagnose precancerous lesions (sensitivity) while at the same time avoiding false positive diagnosis (specificity). In turn, these criteria are dependent on the accuracy of the cytological interpretation. Traditionally, a pathologist may perform a single cell analysis on a biological specimen by looking at the characteristics of individual cell nuclei, or a contextual analysis on the biological specimen by looking for characteristic patterns in the architecture of the cells as they appear on the slide.
Even when performing both single cell and contextual analyses, the conventional Pap smear has false negative rates ranging between 10-50%. This is due in large part to the vast number of cells and objects (typically as many as 100,000 to 200,000) that must be reviewed by a technician to determine the possible existence of a small number of malignant or pre-malignant cells. Thus, Pap smear tests, as well as other tests requiring detailed review of biological material, have suffered from a high false negative rate due to fatigue imposed on the technician.
To facilitate this review process, automated screening systems have been developed. In a typical system, an imager is operated to provide a series of images of a cytological specimen slide, each depicting a different portion of the slide. A processor then processes these images to furnish quantitative and prognostic information about the specimen. The processor can perform either a single cell analysis or a contextual analysis, or both, in providing this diagnostic information. For example, when performing a single cell analysis, the processor may determine such cell characteristics as cytoplasmic area ratio, nuclear integrated optical density, average nuclear optical density, nuclear texture, and cytoplasmic hue. When performing a contextual analysis, the processor may determine such architectural characteristics as (1) average internuclear distances within clusters; (ii) standard deviation of the cytoplasmic grey values; (iii) means of the area of bare nuclei; (iv) standard deviation of the area of the bare nuclei; (v) average cytoplasm area of clusters; and (vi) inverse intercell distances. The results of the single cell and contextual analyses are combined to arrive at a diagnosis that is generally more accurate than if only one of the cell and contextual analyses formed the basis for the diagnosis.
In some automated screening systems, the processor uses the diagnostic information to delineate between “normal” and “suspicious” slides. In the clinical laboratory, only those slides flagged as suspicious would be examined by a cytotechnologist, thus reducing the work load. In other automated screening systems, the processor uses the diagnostic information to delineate between normal and suspicious biological material within each specimen. That is, the processor will focus the cytotechnologist's attention on the most pertinent cells, with the potential to discard the remaining cells from further review. In this case, the screening device uses the diagnostic information to determine the most pertinent biological objects (e.g., the cells and cell clusters mostly likely to have attributes consistent with malignant or pre-malignant cells), and their locations on the slide. This location information is then passed onto a microscope, which automatically proceeds to these locations and centers on the biological objects for review by the cytotechnologist. The cytotechnologist will then electronically mark the biological objects that are the most pertinent (for example, the objects having attributes consistent with malignant or pre-malignant cells) for further review by a pathologist.
In general, the use of automated screening systems has proved to be successful, since the technician's attention is focused on the those slides that are suspicious or on a limited number of more pertinent objects within each slide. No automated device, however, has thus far eliminated false negative and false positive results at sufficiently low cost to be practical. In addition, there is also a commercial aspect that must be taken into account. The cost borne by laboratories to review cytological specimens, such as Pap smear specimens, is tied, at least in part, to the time taken for a technician to review each slide. That is, the more slides that a cytotechnologist must review, or the more time it takes for a technician to review each slide slide, the more cost in labor the laboratory incurs. Conversely, the less slides that a technician must review, and the less time that it takes for the technician to review a slide, the more money the laboratory can save.
The occurrence of false positives sometimes results from biological specimens with low-quality stains. For example, a technician may fail to follow the proper protocol for applying a particular stain to the biological specimens, or if correctly applied, the shelf-life of the stain may have expired. Oftentimes, specimens are not flagged as having a low-quality stain until after they have been manually reviewed by the cytotechnologist, thereby wasting valuable time.
There thus remains a need to provide a more efficient and accurate process for analyzing biological specimens, such as Pap smear specimens, and determining the stain quality of such biological specimens.